Selenium (Se) is an essential trace element that plays a critical role in many biological processes, such as reproduction, thyroid hormone metabolism, DNA synthesis, and protection from oxidative damage and infection. Selenium is incorporated at the catalytic site of various selenium dependent enzymes such as glutathione peroxidase (GPx), thioredoxin reductases, and one methionine-sulfoxidereductase. These selenoenzymes contribute to regulation of metabolic activity, immune function, antioxidant defense, intracellular redox regulation, and mitochondrial function.
The organelle known as the mitochondrion (“MT”) is the main energy source in cells of higher organisms. Mitochondria provide direct and indirect biochemical regulation of a wide array of cellular respiratory, oxidative and metabolic processes. These include electron transport chain (ETC) activity, which drives oxidative phosphorylation to produce metabolic energy in the form of adenosine triphosphate (ATP), and which also underlies a central mitochondrial role in intracellular calcium homeostasis. Mitochondrial respiration occurs on the inner mitochondrial membrane and is achieved by the flow of electrons through the electron transport system, which contains four complexes (complex I, II, III, and IV) with a further complex (complex V) serving as a site for ATP synthesis (ATP synthase). Impairment or reduction of activity of any complex disrupts electron flow and may cause mitochondrial respiratory dysfunction (See, e.g., Schildgen et al., Exp Hematol 2011; 39:666-67510,11; Arthur et al., Mol Neurodegener 2009; 4:37).
Mitochondrial dysfunction leading to cell death, reactive oxygen species production, increased oxidative DNA damage, increased autophagy, and loss of mitochondrial membrane potential has been associated with conditions such as diabetes, obesity, aging related neurodegeneration including Alzheimer's disease, stroke, insulin resistance, and atherosclerosis. An inorganic form of selenium, sodium selenite, has been shown to affect mitochondrial function in certain circumstances. Mehta et al. showed a marker of mitochondrial biogenesis, PGC1a, is increased in ischemic brain tissue and that sodium selenite further increases PGC1a after ischemia and recirculation. (Mehta et al., BMC Neuroscience 2012 13:79). Tirosh et al. showed that a high dose but not an intermediate dose of sodium selenite prevented hapten induced impairment of mitochondrial function due to hapten induced inflammation in colon tissue. (Tirosh et al., Nutrition 2007 23:878). These results suggest that inorganic selenium can impact mitochondrial function in cells undergoing damage. However, some studies have found that sodium selenite is less bioavailable than other forms of selenium calling into question its effectiveness. (Rider et al., J Anim Physiol Anim Nutr (Berl) 2010 94(1):99-110).
In addition, results in the literature indicate that different chemical forms of selenium have different bioactivities. For example, a selenozolidine was more effective at reducing the number of lung tumors than selenomethionine (Poerschke et al, J Biochem Molecular Toxicology 2012 26:344). Barger et al. showed that mice fed different sources of selenium, for example, selenium methionine, sodium selenite and selenized yeast, had differential effects on gene expression and on specific functional pathways of mitochondrial structure and function. (Barger et al, Genes and Nutrition 2012 7:155).
Because of the apparent difference in bioactivity and availability of distinct chemical forms of selenium, there is a need to identify chemical forms of selenium and to characterize their effects on biological processes. Characterization of these effects on biological processes can lead to medicinal regulation of significant biological processes to prevent or combat diseases, such as those diseases linked to mitochondrial dysfunction. Diseases linked to mitochondrial dysfunction may be prevented or treated by administering particular chemical forms of selenium that reduce mitochondrial dysfunction or upregulate mitochondrial function in one or more types of animal or human cells. One explanation for the variation in bioactivity could be that different forms of selenium have different effects on biological pathways at the molecular level.